Viral polymerase inhibitors

ABSTRACT

The present invention relates to viral polymerase inhibitors of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof, processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

FIELD

The present invention relates to viral polymerase inhibitors, in particular inhibitors of viral polymerases within the Flaviviridae family such as hepatitis C virus (HCV), processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

BACKGROUND

The Flaviviridae are a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. The Flaviviridae consist of various genera including: Hepaciviruses (this genus contains only one species, the Hepatitis C virus (HCV), which is composed of many genotypes and subtypes); Flaviviruses (this genus includes the Dengue virus, Japanese Tick-Borne and the Yellow Fever virus and there are some additional Flaviviruses that are unclassified) and Pestiviruses (this genus includes three serotypes of bovine viral diarrhoea virus, but no known human pathogens).

Hepatitis C virus (HCV) is a major cause of viral hepatitis and has infected more than 200 million people worldwide. Hepatitis C virus has a positive-strand RNA genome enclosed in a nucleocapsid and lipid envelope. The HCV genome is approximately 9.6 kb in length and encodes a polyprotein of about 3,000 amino acids. There are at least six major genotypes, which have different geographic distributions. In the United States (US), for example, genotypes 1a and 1b account for about 75% of cases, and genotypes 2 and 3 for 10-20% of cases. Significant differences are observed in the geographic distribution of HCV genotypes. For example, in Europe genotypes 2 and 3 comprise up to one half of cases whereas genotype 3 is thought to dominate in India. In addition, varied genotype distributions can be observed between countries in a particular region as well as in different areas of a given nation. In the US, HCV is the most common chronic blood-borne infection, affecting approximately 3.2 million persons. After infection with HCV, approximately 75-85% of people develop chronic infection, whilst 60-70% develop chronic liver disease. Of these, 5-20% go on to develop cirrhosis over a period of 20-30 years, and, finally, 1-5% succumb to the consequences of chronic infection (liver cancer/cirrhosis).

Until recently, the only treatment option for HCV was 24 or 48 weeks of combination therapy consisting of weekly injections of pegylated interferon (peg-IFN) and oral ribavirin for 24 or 48 weeks. The best treatment response is seen in patients with HCV genotypes 2 and 3, in whom sustained viral response (SVR) rates of approximately 80% can be achieved with 24 weeks of therapy. Patients with HCV genotype 1 remain the most difficult to treat, with SVR rates of approximately 40% after 48 weeks of therapy. In addition to the low response rates, combination peg-IFN/ribavirin therapy is limited by serious side effects, including fatigue, influenza-like symptoms, depression and suicide with peg-IFN, and haemolytic anaemia with ribavirin. Furthermore, peg-IFN/ribavirin therapy is contra-indicated in patients who have depression, anaemia, HCV-related decompensated cirrhosis, alcohol/substance abuse and autoimmune disorders or who are pregnant.

New treatment options for HCV became available in May 2011 with the US launch of the first direct-acting antiviral (DAA) HCV drugs, telaprevir (Vertex Pharmaceuticals) and boceprevir (Merck). Both drugs are protease inhibitors and are approved for the treatment of chronic HCV genotype 1 infection in combination with peg-IFN and ribavirin. Pivotal phase 3 trials demonstrated that the addition of telaprevir or boceprevir to peg-IFN/ribavarin therapy achieved shortened durations of therapy and potent viral suppression, with SVR rates approaching 75% in genotype 1 treatment-naive patients and 30% to 85% in treatment-experienced patients.

However, addition of a third drug to the treatment regimen has resulted in increased adverse events. Telaprevir is associated with an increased incidence of rash and anaemia, while boceprevir is associated with anaemia and dysgeusia. Triple therapy with telaprevir or boceprevir and peg-IFN/ribavirin remains unsuitable for those intolerant to or with contraindications to peg-IFN/ribavirin therapy.

Further, the majority of compounds that are currently in development have a limited spectrum of activity against the various HCV genotypes and, in many cases, are only active against HCV genotypes 1b and/or 1a.

The HCV genome possesses structural (core) and non-structural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. The non-structural proteins are involved in viral genomic replication, with the initial synthesis of RNA carried out by NS5B RNA dependent RNA polymerase. The NS5B protein is a key target for anti-HCV therapy, as it is essential for HCV replication and has no human host equivalent. This protein has been well characterised and is a validated target for drug discovery.

HCV therapy is also anticipated to evolve towards oral multidrug therapy, in which combinations of different DAA drugs with complementary mechanisms of action serve to increase viral suppression and delay or prevent the emergence of resistance.

Due to the limited tolerability, efficacy, side effects and concern over the emergence of resistance there is an ongoing need to find alternative agents for the treatment of HCV, particularly with targeted mechanisms of action such as NS5B inhibitors.

SUMMARY

The inventors have found a new class of NS5B polymerase inhibitors for the treatment of HCV infections.

Compounds of the present invention are therefore considered to be useful in treating and preventing hepatitis C infections when used on their own or in combination with one or more other antiviral agents such as ribavirin, an antiviral nucleoside, polymerase inhibitor, protease inhibitor and/or inhibitor of viral entry, assembly or egress. The combination may also additionally comprise at least one immunomodulatory agent for example an interferon or interferon derivative and/or an inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH).

It is also believed that compounds of the invention will be efficacious in combination with at least one other DAA with a different mechanism of action and a complementary resistance profile (for example an NS5A inhibitor, a nucleoside or nucleotide NS5B inhibitor or a NS3 protease inhibitor) thereby offering an alternative treatment regime for patients not eligible for or treatable with the recently approved triple combination therapy.

According to a first aspect there is provided a compound of formula (I), salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof:

wherein

-   Z₁ and Z₂ are each independently selected from C—H, C-halo,     C—C₁₋₄alkyl, C—C₁₋₄alkylhalo, C—C₁₋₄alkoxy, C—C₁₋₄alkoxyhalo and N; -   R₁ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,     C₁₋₆alkoxy, halo, C₁₋₄alkylhalo, C₁₋₄alkoxyhalo, C₃₋₇cycloalkyl,     C₃₋₇cycloalkenyl, 5-6-membered heterocyclyl and 5-6 membered     heteroaryl and wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,     heterocyclyl and heteroaryl in each occurrence may be optionally     substituted; -   R₂ is H or an optional substituent; -   R₃ is an optionally substituted 6-membered heteroaryl group     containing N in the 2-(ortho) ring position with reference to the     point of attachment or R₃ is an optionally substituted 5-membered     heteroaryl group containing N in the ring position adjacent to the     point of attachment; -   R₄ is H, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, or C₃₋₇cycloalkyl     preferably C₁₋₄alkyl; -   R₅ in each occurrence is independently H or optionally substituted     C₁₋₆alkyl; -   m represents an integer selected from 0, 1, 2, 3, 4, 5 and 6; and -   each (CH₂) moiety when present may be independently optionally     substituted with one or two substituents; -   and further when m is an integer selected from 1, 2, 3, 4, 5 and 6     then one or more (CH₂) may be replaced with O, C═O, NH, optionally     substituted NC₁₋₆alkyl, S, S═O or SO₂.

Optionally substituted 6-membered heteroaryl groups containing N in the 2-(ortho) ring position include 2-pyridyl, 2-pyrimidinyl, 3-pyridazinyl or 2-pyrazinyl.

In one embodiment R₃ is an optionally substituted 2-pyridyl moiety.

Optionally substituted 5-membered heteroaryl groups containing N in the ring position adjacent to the point of attachment include 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 3-triazolyl, 4-triazolyl, 5-tetrazolyl, 2-thiazolyl, 4-thiazolyl, 3-isothiazolyl, 2-thiadiazolyl, 3-thiadiazolyl, 5-thiadiazolyl, 2-oxazolyl, 4-oxazolyl, 3-isoxazolyl, 2-oxadiazolyl, 3-oxadiazolyl and 5-oxadiazolyl.

In one embodiment R₃ is an optionally substituted 2-thiazolyl moiety.

According to a second aspect there is provided a process for producing the compound of formula (I) defined above comprising the step of coupling a compound of formula (II):

with a compound of formula (III) under coupling conditions; wherein

-   W is hydroxyl, mesylate, tosylate, triflate or halo; and -   Z₁, Z₂, R₁, R₂, R₃, R₄, R₅ and (CH₂)_(m) are as previously defined.

Alternatively, the moiety R₂ may be introduced post-coupling of a suitable precursor moiety to a compound of formula (II), for example, a precursor containing a diol or alkene group which is subsequently functionalised to the desired 4-membered heterocyclic ring moiety under suitable ring forming conditions. The compounds of formula (II) are believed to be novel and accordingly, in one embodiment there is provided a compound of formula (II), preferably for use as an intermediate in the process for producing a compound of Formula (I).

The compounds of formula (I) are inhibitors of HCV. In particular, the compounds of formula (I) inhibit RNA synthesis by the RNA dependent RNA polymerase of HCV (the NS5B protein encoded by HCV). NS5B inhibitors have been clinically validated as potential antiviral agents for the treatment of HCV infection.

According to a third aspect, there is provided a pharmaceutical agent comprising the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above, optionally in combination with another HCV antiviral agent.

There is also provided use of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above as a pharmaceutical agent, optionally in combination with another HCV antiviral agent.

There is further provided the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above for use as a pharmaceutical agent, optionally in combination with another HCV antiviral agent.

The pharmaceutical agent may be an antiviral agent.

According to a fourth aspect, there is provided a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a NS5B inhibitor comprising the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above, optionally in combination with another HCV antiviral agent.

There is also provided use of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above as a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a NS5B inhibitor, optionally in combination with another HCV antiviral agent.

There is further provided the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above for use as a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a NS5B inhibitor, optionally in combination with another HCV antiviral agent.

The compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier, optionally in combination with another HCV antiviral agent.

According to a fifth aspect, there is provided a pharmaceutical composition comprising the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and a pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition additionally comprises a therapeutically effective amount of one or more antiviral agents such as at least one other HCV antiviral agent.

According to a sixth aspect, there is provided a method for the treatment of a Flaviviridae viral infection such as a HCV infection which comprises administering an effective amount of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above or the pharmaceutical agent or pharmaceutical composition defined above, optionally in combination with another HCV antiviral agent to a subject in need thereof.

There is also provided use of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above or the pharmaceutical agent or pharmaceutical composition as defined above in the manufacture of a medicament for use in the treatment of a Flaviviridae viral infection such as a HCV infection, optionally in combination with another HCV antiviral agent.

There is further provided use of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above or the pharmaceutical agent or pharmaceutical composition as defined above, optionally in combination with another HCV antiviral agent in the treatment of a Flaviviridae viral infection such as a HCV infection.

There is still further provided the compound of the formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above or the pharmaceutical agent or pharmaceutical composition defined above, optionally in combination with another HCV antiviral agent for use in the treatment of a Flaviviridae viral infection such as a HCV infection.

According to a seventh aspect, there is provided a method of inhibiting the RNA-dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to an effective amount of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above, optionally in combination with another HCV antiviral agent.

According to an eighth aspect, there is provided a method of inhibiting HCV replication comprising exposing a cell infected with HCV to an effective amount of the compound of formula (I) or pharmaceutically acceptable salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof as defined above, optionally in combination with another HCV antiviral agent.

DETAILED DESCRIPTION

The present invention is predicated on the discovery of a new class of compounds that have been shown to inhibit viral polymerases, more particularly NS5B polymerases. Accordingly in one embodiment the compounds of formula (I) are useful in the treatment of Flaviviridae viral infections, particularly, hepatitis C (HCV).

This class of compounds is generally described in Applicant's earlier filed U.S. Ser. No. 13/278,021 and WO2012/051659 (PCT/AU2011/001336). However, when a representative compound of the present invention containing a 2-pyridyl in the R₃ position was compared with its 3-pyridyl analogue, it was unexpectedly found to have improved properties, as described in more detail in the examples which follow.

Definitions

Unless otherwise herein defined, the following terms will be understood to have the general meanings which follow.

The term “C₁₋₆alkyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term “C₁₋₆alkyl” also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C₁₋₄alkyl” and “C₁₋₃alkyl” including methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl are preferred with methyl being particularly preferred.

The term “C₂₋₆alkenyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. Unless the context requires otherwise, the term “C₂₋₆alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C₂₋₄alkenyl” and “C₂₋₃alkenyl” including ethenyl, propenyl and butenyl are preferred with ethenyl being particularly preferred.

The term “C₂₋₆alkynyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl and the like. Unless the context indicates otherwise, the term “C₂₋₆alkynyl” also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. C₂₋₃alkynyl is preferred.

The term “C₃₋₈cycloalkyl” refers to non-aromatic cyclic groups having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C₃₋₆cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred.

The terms “hydroxy” and “hydroxyl” refer to the group —OH.

The term “oxo” refers to the group ═O.

The term “C₁₋₆alkoxy” refers to an alkyl group as defined above covalently bound via an O linkage containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy. “C₁₋₄alkoxy” and “C₁₋₃alkoxy” including methoxy, ethoxy, propoxy and butoxy are preferred with methoxy being particularly preferred.

The term “C₁₋₆alkylhalo” refers to a C₁₋₆alkyl which is substituted with one or more halogens. C₁₋₃alkylhalo groups are preferred, such as for example, —CHF₂ and —CF₃.

The term “C₁₋₆alkoxyhalo” refers to a C₁₋₆alkoxy which is substituted with one or more halogens. C₁₋₃alkoxyhalo groups are preferred, such as for example, —OCHF₂ and —OCF₃.

The term “carboxylate” or “carboxyl” refers to the group —COO⁻ or —COOH.

The term “ester” refers to a carboxyl group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“carboxylC₁₋₆alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on. CO₂C₁₋₃alkyl groups are preferred, such as for example, methylester (CO₂Me), ethylester (CO₂Et) and propylester (CO₂Pr) and includes reverse esters thereof (e.g. —OCOMe, —OCOEt and —OCOPr).

The term “cyano” refers to the group —CN.

The term “nitro” refers to the group —NO₂.

The term “amino” refers to the group —NH₂.

The term “substituted amino” or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on. C₁₋₃alkylamino groups are preferred, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).

The term “disubstituted amino” or “tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a C₁₋₆alkyl group, which may be the same or different (“dialkylamino”), an aryl and alkyl group (“aryl(alkyl)amino”) and so on. Di(C₁₋₃alkyl)amino groups are preferred, such as for example, dimethylamino (NMe₂), diethylamino (NEt₂), dipropylamino (NPr₂) and variations thereof (e.g. N(Me)(Et) and so on).

The term “acyl” or “aldehyde” refers to the group —C(═O)H.

The term “substituted acyl” or “ketone” refers to an acyl group having a hydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on. C₁₋₃alkylacyl groups are preferred.

The term “amido” or “amide” refers to the group —C(O)NH₂.

The term “aminoacyl” refers to the group —NHC(O)H.

The term “substituted amido” or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylamido” or “C₁₋₆alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on. C₁₋₃alkylamide groups are preferred, such as for example, methylamide (—C(O)NHMe), ethylamide (—C(O)NHEt) and propylamide (—C(O)NHPr) and includes reverse amides thereof (e.g. —NHMeC(O)—, —NHEtC(O)— and —NHPrC(O)—).

The term “disubstituted amido” or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C₁₋₆alkyl group (“di(C₁₋₆alkyl)amido” or “di(C₁₋₆alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on. Di(C₁₋₃alkyl)amide groups are preferred, such as for example, dimethylamide (—C(O)NMe₂), diethylamide (—C(O)NEt₂) and dipropylamide ((—C(O)NPr₂) and variations thereof (e.g. —C(O)N(Me)Et and so on) and includes reverse amides thereof.

The term “thiol” refers to the group —SH.

The term “C₁₋₆alkylthio” refers to a thiol group having the hydrogen replaced with a C₁₋₆alkyl group. C₁₋₃alkylthio groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.

The term “thioxo” refers to the group ═S.

The term “sulfinyl” refers to the group —S(═O)H.

The term “substituted sulfinyl” or “sulfoxide” refers to a sulfinyl group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“C₁₋₆alkylsulfinyl” or “C₁₋₆alkylsulfoxide”), an aryl (“arylsulfinyl”), an aralkyl (“aralkyl sulfinyl”) and so on. C₁₋₃alkylsulfinyl groups are preferred, such as for example, —SOmethyl, —SOethyl and —SOpropyl.

The term “sulfonyl” refers to the group —SO₂H.

The term “substituted sulfonyl” refers to a sulfonyl group having the hydrogen replaced with, for example a C₁₋₆alkyl group (“sulfonylC₁₋₆alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on. SulfonylC₁₋₃alkyl groups are preferred, such as for example, —SO₂Me, —SO₂Et and —SO₂Pr.

The term “sulfonylamido” or “sulfonamide” refers to the group —SO₂NH₂.

The term “substituted sulfonamido” or “substituted sulphonamide” refers to an sulfonylamido group having a hydrogen replaced with, for example a C₁₋₆alkyl group (“sulfonylamidoC₁₋₆alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on. SulfonylamidoC₁₋₃alkyl groups are preferred, such as for example, —SO₂NHMe, —SO₂NHEt and —SO₂NHPr and includes reverse sulfonamides thereof (e.g. —NHSO₂Me, —NHSO₂Et and —NHSO₂Pr).

The term “disubstituted sufonamido” or “disubstituted sulphonamide” refers to an sulfonylamido group having the two hydrogens replaced with, for example a C₁₋₆alkyl group, which may be the same or different (“sulfonylamidodi(C₁₋₆alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on. Sulfonylamidodi(C₁₋₃alkyl) groups are preferred, such as for example, —SO₂NMe₂, —SO₂NEt₂ and —SO₂NPr₂ and variations thereof (e.g. —SO₂N(Me)Et and so on) and includes reserve sulfonamides thereof.

The term “sulfate” refers to the group OS(O)₂OH and includes groups having the hydrogen replaced with, for example a C₁₋₆alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on. C₁₋₃sulfates are preferred, such as for example, OS(O)₂OMe, OS(O)₂OEt and OS(O)₂OPr.

The term “sulfonate” refers to the group SO₃H and includes groups having the hydrogen replaced with, for example a C₁₋₆alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on. C₁₋₃sulfonates are preferred, such as for example, SO₃Me, SO₃Et and SO₃Pr.

The term “aryl” refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri-cyclic ring system. The aromatic ring or ring system is generally composed of 6 to 10 carbon atoms. Examples of aryl groups include but are not limited to phenyl, biphenyl, naphthyl and tetrahydronaphthyl. 6-membered aryls such as phenyl are preferred. The term “alkylaryl” refers to C₁₋₆alkylaryl such as benzyl.

The term “alkoxyaryl” refers to C₁₋₆alkyloxyaryl such as benzyloxy.

The term “heterocyclyl” refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3 or 4 are ring heteroatoms each heteroatom being independently selected from O, S and N.

In this context, the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10-membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, the term “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered rings), piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5-membered rings), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered rings), oxane (tetrahydropyran), dihydropyran, pyran (6-membered rings), oxepin (7-membered ring); those containing two oxygen atoms such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing three oxygen atoms such as trioxane (6-membered ring); those containing one sulfur atom such as thiirane (3-membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepane (7-membered ring); those containing one nitrogen and one oxygen atom such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered rings), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6-membered rings); those containing one nitrogen and one sulfur atom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen and one sulfur atom such as oxathiazine (6-membered ring).

Heterocyclyls also encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.

The term “aromatic heterocyclyl” may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”. The heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.

“Heteroaryl” is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls. The term “pseudoaromatic” refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings. The term aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.

Examples of 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.

Examples of 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).

Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like). Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; l) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups. A further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.

Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

Examples of heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.

Examples of aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

The term “non-aromatic heterocyclyl” encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.

Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.

Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like.

Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl and the like.

Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl and the like.

Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems. Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like. Examples of non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.

The term “halo” refers to fluoro, chloro, bromo or iodo.

Unless otherwise defined, the term “optionally substituted” or “optional substituent” as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups selected from the group consisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, hydroxyl, oxo, C₁₋₆alkoxy, aryloxy, C₁₋₆alkoxyaryl, halo, C₁₋₆alkylhalo (such as CF₃ and CHF₂), C₁₋₆alkoxyhalo (such as OCF₃ and OCHF₂), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arC₁₋₆alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case of heterocycles containing N may also include but are not limited to C₁₋₆alkyl i.e. N—C₁₋₃alkyl, more preferably methyl particularly N-methyl.

It will be understood that suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof.

Compounds

The present invention relates to compounds of formula (I), salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof.

In one embodiment (CH₂)_(m) represents an optionally substituted methylenyl (i.e. m=1), ethylenyl (i.e. m=2) or propylenyl (i.e. m=3) moiety, preferably m is 1 or 2.

In one embodiment each (CH₂)_(m) when present may be independently optionally substituted with one or two optional substituents as previously defined and preferably selected from the group consisting of halo, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆alkenyl, haloC₁₋₃alkyl, OH, ═O, optionally substituted C₁₋₆alkoxy, haloC₁₋₃alkoxyl, CO₂H, optionally substituted esters of general formula C(═O)OC₁₋₆alkyl, CN, NO₂, NH₂, NHC₁₋₃alkyl, N(C₁₋₃alkyl)₂, optionally substituted amides of general formula NHC(═O)C₁₋₆alkyl, an optionally substituted C₃₋₇cycloalkyl, an optionally substituted C₆₋₁₀aryl and an optionally substituted 4-10-membered heterocyclyl.

In one embodiment R₂ is H.

In another embodiment R₂ is an optional substituent selected from optionally substituted C₁₋₃alkyl, halo, haloC₁₋₃alkyl, OH, C₁₋₃alkoxyl, haloC₁₋₃alkoxyl, CO₂H, CO₂C₁₋₃alkyl, NH₂, NHC₁₋₃alkyl, N(C₁₋₃alkyl)₂, NHC(═O)C₁₋₃alkyl, an optionally substituted C₃₋₇cycloalkyl, an optionally substituted C₆₋₁₀aryl, an optionally substituted 4-10-membered heterocyclyl including 4-, 5- and 6-monocyclic heterocyclyls, 5-6-membered monocyclic heteroaryls, 8-10-membered fused bicyclic heterocyclyls and 8-10-membered fused bicyclic heteroaryls.

In one embodiment, R₂ is an optional substituent selected from the group consisting of C₁₋₃alkyl (preferably methyl), C₁₋₃alkoxyl (preferably methoxy), halo (preferably F), haloC₁₋₃alkyl (preferably CHF₂ or CF₃) and an optionally substituted 4-membered heterocyclyl such as an oxygen or nitrogen containing 4-membered heterocyclyl (preferably oxetane or azetidine).

In one embodiment R₂ is selected from methyl, methoxy, F and CHF₂.

In yet another embodiment R₂ is an optionally substituted oxetane or azetidine wherein the optional substituents are selected from the group consisting of optionally substituted C₁₋₃alkyl (preferably methyl which may be further optionally substituted with NHC(═O)OC₁₋₄alkyl, preferably NHC(═O)O-tert-butyl), C₁₋₃alkoxyl (preferably methoxy), CO₂C₁₋₄alkyl (preferably CO₂-tert-butyl) and C(═O)C₁₋₃alkyl (preferably C(═O)CH₃)

In another embodiment Z₁ and Z₂ are both C—H.

In one embodiment R₁ is selected from optionally substituted C₁₋₃alkyl, C₁₋₃alkoxyl and C₃₋₅cycloalkyl. In a particularly preferred embodiment R₁ is cyclopropyl.

In one embodiment R₄ is an optionally substituted C₁₋₃alkyl, preferably unsubstituted methyl.

In another embodiment, R₅ is optionally substituted C₁₋₆alkyl preferably C₁₋₃alkyl optionally substituted with halo such as CF₃ or CHF₂ with methyl being particularly preferred.

In a particularly preferred embodiment R₃ is a 2-pyridyl moiety optionally substituted with 1, 2 or 3 substituents, with 1 or 2 substituents independently selected from the group consisting of C₁₋₃alkyl, halo, haloC₁₋₃alkyl, OH, C₁₋₃alkoxyl, haloC₁₋₃alkoxyl, CO₂H, CO₂C₁₋₃alkyl, NH₂, NHC₁₋₃alkyl and N(C₁₋₃alkyl)₂. In one embodiment the substituents are independently selected from C₁₋₃alkyl, halo and haloC₁₋₃alkyl. In a particularly preferred embodiment R₃ is a 2-pyridyl moiety optionally substituted with 1 or two substituents independently selected from C₁₋₃alkyl (preferably methyl) and halo (preferably Cl).

In still another embodiment the 2-pyridyl is para-substituted.

In one embodiment the compound is of formula (I) and is selected from the group consisting of:

salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof wherein the compounds are named as follows:

-   2)     5-cyclopropyl-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   3)     5-cyclopropyl-6-[(2,2-difluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   4)     5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide; -   5)     5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   6)     5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   7)     5-cyclopropyl-6-[(2-fluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   8)     2-(5-chloropyridin-2-yl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide; -   9)     2-(5-chloropyridin-2-yl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2H-indazole-3-carboxamide; -   10)     5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   11)     5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; -   13)     5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylthiazol-2-yl)indazole-3-carboxamide; -   14)     5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(2-pyridyl)indazole-3-carboxamide; -   15)     2-(5-chloro-4-methyl-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]indazole-3-carboxamide; -   16) tert-butyl     3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]azetidine-1-carboxylate; -   17)     6-[2-(1-acetylazetidin-3-yl)ethyl-methylsulfonyl-amino]-5-cyclopropyl-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide; -   18)     5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide; -   19)     2-(5-chloro-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methylsulfonyl-[2-(oxetan-3-yl)ethyl]amino]indazole-3-carboxamide;     and -   20) tert-butyl     N-[[3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]oxetan-3-yl]methyl]carbamate.

In one embodiment the compound is of formula (II) and is selected from the group consisting of:

and salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof wherein the compounds are named as follows:

-   1)     5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide;     and -   12)     2-(5-chloro-2-pyridyl)-5-cyclopropyl-6-(methanesulfonamido)-N-methyl-indazole-3-carboxamide.

The compounds of the invention may also be prepared as salts which are pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic, toluenesulfonic, benzenesulfonic, isethionic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric and orotic acids. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.

The salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid.

It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF) and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Additionally, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds of the present invention are also considered to be disclosed herein.

It will be understood that compounds of formula (I) may possess a chiral centre and may therefore exist as an isomer such as a racemate or an R- or S-enantiomer. The compounds may therefore be used as a purified enantiomer or diastereomer, or as a mixture of any ratio thereof. The isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has a carbon-carbon double bond, it may occur in Z- or E-form and all isomeric forms of the compounds being included in the present invention.

This invention also encompasses prodrugs of the compounds of formula (I). The term “pro-drug” is used herein in its broadest sense to include those compounds which are converted in vivo to the compound of formula (I). Use of the prodrug strategy optimises the delivery of the drug to its site of action. In one embodiment, compounds of formula (I) having free amino, amido, hydroxyl, or carboxylic acid groups can be converted into prodrugs. Prodrugs include compounds wherein carbonates, carbamates, amide and alkyl esters which are covalently bonded to the above substituents of compounds of the present invention through a carbonyl carbon prodrug sidechain. Prodrugs may also include N-oxides of ring nitrogen atoms in formula (I).

Viral Polymerase Inhibition

The ability of the compounds of formula (I) to inhibit RNA synthesis by the RNA dependent RNA polymerase of HCV (NS5B) can be demonstrated by any assay capable of measuring RNA dependent RNA polymerase activity. A suitable assay is described in the examples.

While the invention is described with particular reference to compounds having inhibitory activity against a HCV NS5B polymerase, it will be understood that other polymerases can, if desired, be substituted in whole or in part for the HCV polymerase herein described. For example, one microbial polymerase target is HCV NS5B which is the viral RNA-dependent RNA polymerase (RdRp) that is responsible for viral replications. HCV NS5B protein, is released from a polyprotein and is involved in the synthesis of double-stranded RNA from a single-stranded viral RNA genome. It is believed that the replication and/or reproduction of HCV virus may be inhibited or prevented through the inhibition of NS5B and suppress or prevent the formation of the double-stranded HCV RNA.

To demonstrate that the compounds of formula (I) act by specific inhibition of NS5B, the compounds may be tested for the lack of inhibitory activity in an assay measuring the activity of an RNA-dependent RNA polymerase other than HCV polymerase or in a DNA dependent RNA polymerase assay.

Pharmaceutical Compositions

The invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The pharmaceutical composition may further comprise or be administered in combination with one or more other antiviral agents such as Ribavirin (Copegus® or Rebetol®), an antiviral nucleoside inhibitor of NS5B polymerase (such as 4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine; PSI-7977; PSI-938; RG7128 or mericitabine; IDX-184; INX-189 and other such agents that may be developed), a non-nucleoside inhibitor of NS5B polymerase (such as GS-9190 or tegobuvir; PF-868554 or filibuvir; VX-222; IDX-375; ABT-072; ABT-333; ANA-598 or setrobuvir; BI207127; JTK-853; GS-9669; and other such agents that may be developed), a NS3/4a protease inhibitor (such as telaprevir or Incivek®; boceprevir or Victrelis®; BI-201335; TMC-435; RG-7227 or danoprevir; MK-7009 or vaniprevir; GS-9451; GS-9256; BMS-650032; ACH-1625; ACH-2684; MK-5172; ABT-450; IDX-320; SCH-900518 and other such agents that may be developed), an NS5A inhibitor (such as BMS-790052 (daclatasvir); GS-5885; ABT-267; PPI-461; ACH-2928; GSK2336805 and other such agents that may be developed) and/or inhibitor of viral entry, assembly or egress. The composition may also additionally comprise at least one immunomodulatory agent for example an interferon or interferon derivative such as interferon alpha 2B (such as Intron® A interferon available from Schering Corp., Kenilworth, N.J.), pegylated interferon alpha 2A (such as Pegasys® available from Hoffmann-LaRoche, Nutley, N.J.), pegylated interferon alpha 2B (such as Peg-Intron® available from Schering Corp., Kenilworth, N.J.), consensus interferon (such as interferon alphacon-1, or Infergen® available from Valeant Pharmaceuticals, Costa Mesa, Calif.), interferon alpha 2A, recombinant interferon alpha 2A (such as Roferon® available from Hoffmann-LaRoche, Nutley, N.J.), or lymphoblastoid interferon tau, and/or an inhibitor of inosine-5′-monophosphate dehydrogenase (IMPDH) and other large or small molecules known to modulate host immune responses.

Accordingly, in one embodiment of the pharmaceutical composition, the other antiviral agent is Ribavarin optionally in combination with peg-IFN.

In another embodiment, the other antiviral agent is an NS5B inhibitor, more particularly a nucleoside inhibitor such as the bicyclic nucleosides and nucleotides of the general formula described in WO2010/002877, for example, 4-amino-7-(2-C′-methyl-β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine.

In yet another embodiment, the other antiviral agent is an NS3/4A protease inhibitor such as telaprevir (VX-950) or Incivek®; boceprevir or Victrelis®; BI-201335; TMC-435; RG-7227 or danoprevir; MK-7009 or vaniprevir; GS-9451; GS-9256; BMS-650032; ACH-1625; ACH-2684; MK-5172; ABT-450; IDX-320; SCH-900518, particularly telaprevir (VX-950).

In still another embodiment, the other antiviral agent is an NS5A inhibitor such as BMS-790052 (daclatasvir); GS-5885; ABT-267; PPI-461; ACH-2928; GSK2336805, particularly BMS-790052 (daclatasvir).

It will be understood that combined administration of the compounds of the invention with the other antiviral agent may be concurrent, sequential or separate administration.

The term “composition” is intended to include the formulation of an active ingredient with conventional carriers and excipients, and also with encapsulating materials as the carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the encapsulation carrier. Any carrier must be “pharmaceutically acceptable” meaning that it is compatible with the other ingredients of the composition and is not deleterious to a subject. The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation (See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins).

The pharmaceutical composition includes those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

The compositions according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi.

The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the compounds, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients such as these enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.

When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

The amount of active compound in therapeutically useful compositions should be sufficient that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound (s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.

In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

When desired, formulations adapted to give sustained release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of a HCV viral infection in living subjects having a diseased condition in which bodily health is impaired.

The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

Compositions comprising compounds of the invention formulated for oral delivery either alone or in combination with another HCV antiviral agent are particularly preferred.

As such, in one embodiment there is provided a pharmaceutical composition comprising a compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally another HCV antiviral agent selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor. In a further embodiment the pharmaceutical composition may additionally comprising at least one immunomodulatory agent such as peg-IFN. In still a further particularly preferred embodiment, the pharmaceutical composition is administered in an effective amount to a subject in need of treatment for a HCV infection.

Methods of Treatment

The compounds of formula (I) may be used in the treatment of a Flaviviridae viral infection such as a HCV infection.

Generally, the term “treatment” means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and includes: (a) inhibiting the viral infection, i.e. arresting its development or further development; (b) relieving or ameliorating the effects of the viral infection, i.e. cause regression of the effects of the viral infection; (c) reducing the incidence or the viral infection or (d) preventing the infection from occurring in a subject, tissue or cell predisposed to the viral infection disease or at risk thereof, but has not yet been diagnosed with a protective pharmacological and/or physiological effect so that the viral infection does not develop or occur in the subject, tissue or cell.

The prevention of hepatitis C means, for example, administration of a pharmaceutical agent to a subject found to carry a HCV by a test and the like but without a symptom of infection, or to a subject who shows an improved disease state of hepatitis after a treatment of hepatitis C, but who still carries a HCV and is associated with a risk of recurrence of hepatitis.

The term “subject” as used herein refers to any animal, in particular mammals such as humans having a disease or condition which requires treatment with the compound of formula (I).

The term “administering” refers to providing the compound or pharmaceutical composition of the invention to a subject suffering from or at risk of the diseases or conditions to be treated or prevented.

The term “viral infection” refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.

The term “Flaviviridae virus” refers to a virus of the family Flaviviridae, which family includes the Hepacivirus Flavivirus and Pestivirus or hepatitis C-like virus genera. A representative species of the genus of hepatitis C-like viruses is hepatitis C virus.

Dosages

The term “therapeutically effective amount” refers to the amount of the compound of formula (I) that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician.

In the prevention or treatment of HCV infections or diseases an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. The dosage may be selected, for example to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the subject to be treated.

It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the subject undergoing therapy.

It will further be understood that when the compounds of the invention are to be administered in combination with one or more HCV antiviral agents the dosage forms and levels may be formulated for either concurrent, sequential or separate administration or a combination thereof.

General Method(s)

Compounds of the invention may be generally prepared by the following general method(s).

Compounds of formula (I) may be generally synthesized via a synthetic intermediate of general formula (II) as previously described. Suitable coupling conditions will be familiar to those skilled in the art and include, but are not limited to, alkylation and Mitsunobu reactions.

It will be understood that unless otherwise defined each moiety having a substitutable hydrogen such as for example, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, in each occurrence as described in the general schemes and methods which follow may be optionally substituted.

It will also be understood that the particular examples which are described herein may undergo further functionalisation using methods known in the art to form further examples of compounds of the invention.

General Method A

Scheme 1: where R₁ may be, for example, C₃₋₆cycloalkyl such as cyclopropyl, C₁₋₆alkyl including methyl, ethyl, n-propyl and iso-propyl, halo or C₁₋₆alkoxy including methoxy, ethoxy, n-propoxy and iso-propoxy; R₃ is an optionally substituted 6-membered heteroaryl group containing N in the 2-(ortho) ring position; R₄ may be, for example, H or C₁₋₆alkyl; R₅ may be, for example, C₁₋₆alkyl including methyl, ethyl, n-propyl and iso-propyl preferably methyl or C₁₋₃alkylhalo (i.e. C₁₋₃alkyl substituted with halo such as CF₃ or CHF₂) and R₂ is H or an optional substituent as previously defined. Synthesis of Intermediate I

-   Step a) The arylaldehyde was nitrated using a mixture of fuming     nitric acid and sulfuric acid to give a mixture of mono-, di- and     tri-nitrated products. -   Step b) The mono-nitrohaloarylaldehyde was separated by conventional     separation techniques (e.g. column chromatography) and again     subjected to the nitrating conditions described above to give the     corresponding dinitroarylhaloarylaldehyde. -   Step c) The dinitroarylhaoloaldehyde was reacted with a suitably     substituted boronic acid or boronic acid derivative in the presence     of a suitable catalyst (e.g. tetrakistriphenylphosphinepalladium(0))     and a suitable base (e.g. sodium carbonate) in a suitable solvent     (e.g. toluene) as described by Miyaura and. Suzuki (see Miyaura, N.;     Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866-867) to give the     corresponding dinitroaldehyde. -   Step d) The dinitroaldehyde is treated with a suitably substituted     primary heteroarylamine (e.g. a pyridin-2-amine such as     5-C₁₋₃alkyl-pyridin-2-amine or 5-halo-pyridin-2-amine) in a suitable     solvent (e.g. EtOH) to give the corresponding imine, which is then     treated in the same reaction with triphenylphosphine to give the     corresponding nitroindazole where R₃ is an optionally substituted     6-membered heteroaryl group containing N in the 2-(ortho) ring     position. -   Step e) The nitroindazole derived from step d-ii) was treated with a     suitable halogenating reagent (e.g. N-bromosuccinimide) in a     suitable solvent (e.g. DMF) to give the corresponding     halonitroindazole. -   Step f) The halonitroindazole derived from step e-ii) was dissolved     in a suitable solvent (e.g. THF) and treated with a suitable primary     amine in the presence of a suitable catalyst (e.g.     tetrakis(triphenylphosphine)palladium(0) and carbon monoxide to     give, on work-up, the corresponding nitroindazoleamide. -   Step g) The nitroindazoleamide can then be reduced to the     corresponding nitroindazoleamine using standard conditions normally     associated with the reduction of an arylnitro-group to an aniline     (e.g. iron in the presence of an aqueous alcoholic solvent). -   Step h) The amino analogue was first converted to the bis-sulfonyl     analogue using standard sulfonylation conditions with an activated     sulfonic acid (e.g. methanesulfonyl chloride) and base (e.g. DIPEA)     in an organic solvent (e.g. DCM). The bis-sulfonyl analogue then     underwent hydrolysis using base (e.g. potassium hydroxide) in     aqueous alcoholic solvent (e.g. EtOH) to give the desired     sulfonamide. Alternatively, the amino analogue was converted     directly to the desired sulphonamide by reaction with the activated     sulfonic acid (e.g. difluoromethanesulfonyl chloride) in a basic     organic solvent (e.g. pyridine).     Coupling Conditions -   Step i) The compounds of general formula (I) may then be generally     prepared from Intermediate (I) i.e. compound of formula (II) as     previously defined by: (i) coupling an optionally substituted     alkyl-halo/triflate/tosylate/mesylate moiety under alkylation     conditions i.e. the sulphonamide compound of formula (II) is     dissolved/suspended in a suitable solvent (e.g. ACN) and treated     with a suitable alkyl mesylate, triflate, tosylate or halide in the     presence of a suitable base (e.g. potassium carbonate) to give, upon     work-up, the corresponding alkylated sulphonamide of formula (I); or     alternatively, (ii) coupling a hydroxylated precursor moiety under     Mitsunobu reaction conditions wherein the sulphonamide compound of     formula (II) and a suitably substituted primary or secondary alcohol     in a suitable solvent (e.g. THF) is treated with triphenylphosphine     and a suitable di-imide or di-imide equivalent (e.g. DIAD) to give,     upon work-up, the corresponding substituted sulphonamide of formula     (I).

It will be understood that the precursor moieties i.e. of general formula (III) as previously defined may contain, for example, an optionally substituted 4-membered heterocyclic ring or alternatively, the optionally substituted 4-membered heterocyclic ring may be introduced into a suitable precursor component e.g. a diol or alkene, of the compound by undergoing further functionalisation using methods known in the art.

In one embodiment the process comprises the step of coupling a compound of formula (II):

with a compound of formula (III) under coupling conditions; wherein

-   W is hydroxyl, mesylate, tosylate, triflate or halo; and -   Z₁, Z₂, R₁, R₂, R₃, R₄, R₅ and (CH)_(m) are as previously defined.

The compound of formula (II) may be produced from a compound of formula (IX) using sulfonylation conditions:

wherein R₁, R₃, R₄ and R₅ are as previously defined.

The compound of formula (IX) may be produced by reducing the nitro (NO₂) group of the compound of formula (VIII) to an amino (NH₂) group under reduction conditions:

wherein R₁, R₃ and R₄ are as previously defined.

The compound of formula (VIII) may be produced by reacting a compound of formula (VII) with a primary amine of formula NH₂—R₄ in the presence of a catalyst and carbon monoxide:

wherein R₁, R₃ and R₄ are as previously defined.

The compound of formula (VII) may be produced by reacting a compound of formula (VI) with a halogenating reagent:

wherein R₁, R₃ and R₄ are as previously defined.

The compound of formula (VI) may be produced by reacting a compound of formula (IV) with an optionally substituted compound of formula (V) in the presence of triphenylphosphine:

wherein Y is an independently selected substituent;

-   q is an integer 0, 1, 2, 3 or 4; and -   R₁ and R₃ are as previously defined.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described.

The invention will now be described without limitation by reference to the non-limiting examples which follow.

Examples

Synthetic Methods

¹H NMR spectra were recorded on either a Brüker Avance DRX 400, AC 200 or AM 300 spectrometer. Spectra were recorded in deuterated solvents (CDCl₃, MeOD, DMSO, CD₃CN, or Acetone) using the residual solvent peak as a reference. Chemical shifts are reported on the δ scale in parts per million (ppm) using the following conventions to assign the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet) and prefixed br (broad). Mass spectra (ESI) were recorded on either a Micromass Platform QMS or Thermo Finnigan LCQ Advantage spectrometer. Flash chromatography was performed on 40-63 μm silica gel 60 (Merck No. 9385). Automated flash chromatography was performed either on a Combi-Flash™ purification system using Combi-Flash™ silica gel columns or on a Biotage SP4 purification system using either GraceResolv™ silica gel cartridges, Grace Reveleris™ C-18 reverse phase silica gel cartridges or Biotage SNAP™ C-18 reverse phase silica gel cartridges. Preparative HPLC was carried out using either a Gilson 322 pump with a Gilson 215 liquid handler and a HP1100 PDA detector or an Agilent 1200 Series mass detected preparative LCMS using a Varian XRs C-18 100×21.2 mm column. Unless otherwise specified, the HPLC systems employed Phenomenex C8(2) columns using either acetonitrile or acetonitrile containing 0.06% TFA in water, water containing 0.1% TFA or water containing 0.1% formic acid.

During the reactions a number of the moieties may need to be protected. Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. The abbreviations used in the Examples are as follows unless indicated otherwise:

-   Ac: acetyl -   ACN: acetonitrile -   aq.: aqueous -   conc.: concentrated -   CV: column volume -   d. day -   dba: dibenzylideneacetone -   DCM: dichloromethane -   DIPEA: N, N-diisopropylethylamine -   DMF: N,N-dimethylformamide -   DMSO: dimethylsulfoxide -   dppf: 1,1′-bis(diphenylphosphino)ferrocene -   EtOAc: ethyl Acetate -   EtOH: ethanol -   ESI: electrospray ionisation -   h: hour(s) -   HATU: 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium     hexafluorophosphate -   HPLC: high performance liquid chromatography -   LCMS: liquid chromatography coupled mass spectrometry -   min: minute(s) -   MeOH: methanol -   MS: mass spectrometry -   NBS: N-bromosuccinimide -   NMR: nuclear magnetic resonance -   PyBOP: benzotriazol-1-yl-oxytripyrrolidinophosphonium     hexafluorophosphate -   s: second(s) -   SM: starting material -   RT: room temperature -   TEA: triethylamine -   THF: tetrahydrofuran -   TFA: trifluoroacetic acid -   TLC: thin-layer chromatography

Examples

Compound(s) of Formula (II) where R₃ is an Optionally Substituted 6-membered Heteroaryl Group Containing N in the 2-(Ortho) Ring Position

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (1)

5-Bromo-2-nitrobenzaldehyde (ii): To ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid (200 mL) dropwise followed by 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise over 15 min. The reaction mixture was stirred for 10 min and then poured carefully over ice-water. The resulting solids were filtered and then purified by flash column chromatography on silica gel, eluting with EtOAc:n-hexane (gradient elution from 1% to 20% v/v) to give (ii) (60 g, 48%).

5-Bromo-2,4-dinitrobenzaldehyde (iii): To ice cold conc. sulphuric acid (360 mL) was added fuming nitric acid (180 mL) dropwise followed by (ii) (60 g, 0.26 mol) dropwise over 15 min. The reaction mixture was stirred for 10 min and then allowed to warm to RT. After 30 min, the reaction mixture was heated at 45° C. for 2 h and then at 50° C. for 3 h and then allowed to cool to RT. The reaction mixture was then poured carefully over ice-water and the organics were extracted into chloroform (500 mL). The volatiles were dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with EtOAc:n-hexane (gradient elution from 5% to 30% v/v) to give (iii) (5.1 g, 7%).

5-Cyclopropyl-2,4-dinitrobenzaldehyde (iv): To a stirred solution of (iii) (3 g, 10.9 mmol) in toluene (75 mL) was added a solution of sodium carbonate (2.29 g, 21.8 mmol) in water (15 mL). The mixture was sparged with nitrogen for 10 min whereupon cyclopropyl boronic acid (1.4 g, 16.4 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.25 g, 0.22 mmol) were added and the reaction mixture was heated at reflux and progress monitored by TLC. After heating for 6 h the reaction was then cooled to RT and diluted with EtOAc (100 mL). The organic layer was separated and concentrated in vacuo. Purification of the residue by column chromatography on silica gel to gave (iv) (2 g, 78%).

5-Cyclopropyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole (v): To a stirred solution of (iv) (50 mg, 0.212 mmol) in EtOH (750 mL) was added 5-methylpyridin-2-amine (25 mg, 0.23 mmol) and the resultant solution stirred at RT for 2d, after which time a solid precipitated from solution. Triphenylphosphine (167 mg, 0.64 mmol) was added in a single portion and the reaction then heated at 100° C. in a sealed tube for 4 h. Upon cooling to RT, the reaction mixture was diluted with DCM (2 mL) and the organics were washed with aq. 30% hydrogen peroxide solution (2 mL). The organics were separated and filtered through a plug of MgSO₄ and then purified by automated column chromatography (Biotage SP4, Grace 4 g silica cartridge) eluting with EtOAc:n-heptane (gradient elution, 0% equil. (2 CV), 0% (1 CV), 0 to 100% (35 CV), 100% (5 CV)) to give (v) (27 mg, 43%). ESI-MS: calculated [M+H]+ 295.1, observed [M+H]⁺ 295.2.

3-Bromo-5-cyclopropyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole (vi): To a solution of (v) (1.08 g, 3.67 mmol) in DMF (15 mL) was added N-bromosuccinimide (780 mg, 4.40 mmol) and the resulting mixture stirred at 80° C. for 1.5 h. The reaction mixture was then cooled to RT and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with aq. saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic phase was dried (MgSO₄) and the volatiles removed in vacuo to give (vi) (1.37 g, >99%). ESI-MS: calculated [M+H]⁺ 373.0/375.0, observed [M+H]⁺ 373.1/375.1

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-nitro-2H-indazole-3-carboxamide (vii): Compound (vi) (5.80 g, 16.0 mmol), methylamine (2M solution in THF, 120 mL, 230 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.00 g, 1.73 mmol) were placed in a medium pressure reaction vessel. The mixture was degassed and purged with carbon monoxide gas several times and then stirred at 70° C. under 40 psi of CO(g) for 1.5 hr. After cooling to RT, the resulting suspension was filtered and washed with EtOAc. The solid was set aside and the filtrate was concentrated under reduced pressure. The residue was triturated with EtOAc and the solids separated by filtration. The combined solids were dried in vacuo to give (vii) (6.00 g, >100%), which was used in subsequent steps without purification. ESI-MS: calculated [M+H]⁺ 352.1, observed [M+1-1]⁺352.1.

6-Amino-5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide (viii): To a suspension of (vii) (5.6 g, 16.0 mmol) in EtOH (150 mL) and water (30 mL) was added ammonium chloride (6.25 g, 112.8 mmol) followed by iron powder (6.00 g, 112 mmol). The mixture was heated to 80° C. and stirred for 1.5 h whereupon the reaction mixture was filtered through celite, washed with MeOH (50 mL) and the combined filtrate then concentrated in vacuo. The residue was suspended in water and the solid separated by filtration. The residual solid was dried in vacuo at 50° C. for 12 h to give (viii) (2.75 g, 53% over 2 steps from (vi)). ESI-MS: calculated [M+H]⁺ 322.2 observed [M+H]⁺ 322.2.

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (1): To a suspension of (viii) (2.75 g, 8.6 mmol) in DCM (30 mL) at 0° C. was added DIPEA (4.40 mL, 25.0 mmol) followed by methanesulfonyl chloride (3.30 mL, 42.0 mmol). The reaction mixture was stirred at RT for 1 h and then washed with aq. sat'd. NaHCO₃ (50 mL), brine (50 mL) and dried (MgSO₄). Removal of solvent in vacuo gave the crude product, which was then dissolved in EtOH (100 mL) and 1,4-dioxane (20 mL). To the resultant solution was added KOH (˜10 eq) portionwise at RT until the pH of the reaction mixture was between 8 and 9. The reaction mixture was then slowly neutralised by addition of 1M HCl (aq) and volatiles removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (50 mL). The organic phase was dried (MgSO₄), concentrated in vacuo and the solid residue then triturated with EtOAc. The solid was separated by filtration and dried in a stream of air and purified further by automated column chromatography (Biotage SP4, 12 g Grace Resolve cartridge) eluting with EtOAc:n-heptane (gradient elution from 60% to 100%. v/v) to give Compound (1) (2.42 g, 72%). ESI-MS: calculated [M+H]⁺ 400.1 observed [M+H]⁺ 400.1. ¹H NMR (400 MHz, CDCl₃) δ 8.94 (brd, J=3.9 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.17 (s, 1H), 3.18 (s, 3H), 3.09 (d, J=4.7 Hz, 3H), 2.50 (s, 3H), 1.84-1.76 (m, 1H), 1.15-1.04 (m, 2H), 0.84-0.74 (m, 2H).

Compounds of Formula (III) for Coupling to Compounds of Formula (II)

An extensive selection of suitable compounds of formula (III) for coupling to compounds of formula (II) under suitable conditions, particularly alkylation and Mitsunobu conditions, are available from commercial suppliers or will be familiar to those in the art. A further diversity of compounds of formula (III) however may be prepared according to one or more of the following methods.

Scheme 2: where X is O or NR where R is H or an optional substituent, R′ is alkyl and R″ is an optional substituent.

-   Step a) A suitably substituted alkylphosphonate is treated with a     suitable base (e.g. potassium tert-butoxide) in a suitable solvent     (e.g. THF) to give the corresponding phosphonium ylide. A     substituted cyclic ketone can be added to the resultant ylide to     form, on work-up, the corresponding α,β-unsaturated ester. -   Step b) The α,β-unsaturated ester derived from step a) can be     reduced to the corresponding alkyl ester using standard     hydrogenation conditions such as hydrogen gas in the presence of a     suitable catalyst (e.g. 10% palladium on carbon) and a suitable     solvent (e.g. ethanol). -   Step c) The ester derived from step b) can be reduced to the     corresponding alcohol using a suitable reducing agent (e.g. lithium     borohydride) in a suitable solvent (e.g. diethyl ether).

2-(oxetan-3-yl)propan-1-ol

Ethyl 2-(oxetan-3-ylidene)propanoate (i): To a solution of triethyl 2-phosphonopropionate (800 mg, 3.4 mmol) in anhydrous THF (3 mL) was added potassium tert-butoxide (340 mg, 3.1 mmol). The reaction was stirred for 1 h at RT then oxetan-3-one (CAS-RN 6704-31-0, available from commercial suppliers, 220 mg, 3.1 mmol) added in a single portion. The reaction was heated at reflux for 20 h then cooled to RT and adsorbed onto silica gel. Purification by automated column chromatography (Biotage SP4) on silica gel (12 g Grace cartridges) eluting with EtOAc: n-heptane (gradient elution, 0% (equil., 5 CV), 0% (5 CV) 0-100% (25 CV), 100% EtOAc (10 CV)) afforded (i) (151 mg, 31%).

¹H NMR (400 MHz, CDCl₃) δ 5.44-5.37 (m, 2H), 5.30-5.23 (m, 2H), 4.17 (q, J=7.2 Hz, 2H), 1.68 (quint, J=1.8 Hz, 3H), 1.27 (t, J=7.2 Hz, 3H).

Ethyl 2-(oxetan-3-yl)propanoate (ii): To a solution of (i) (151 mg, 0.97 mmol) in EtOH (54 mL) was added 10% Pd/C (50 mg, 0.05 mmol). The reaction was degassed and purged with hydrogen at balloon pressure (×3) then stirred under hydrogen at RT for 16 h. The reaction mixture was filtered and the residue washed with acetonitrile (10 mL). The combined organics were concentrated in vacuo and the residue, (ii) (148 mg), was used without further purification.

2-(Oxetan-3-yl)propan-1-ol: To a suspension of lithium borohydride (40 mg, 1.87 mmol) in anhydrous Et₂O (2.5 mL) at 0° C. was added to a solution of crude (ii) (148 mg, 0.94 mmol) in anhydrous Et₂O (2.5 mL). The reaction was warmed to RT and stirred for 18 h. Water (15 mL) was added cautiously to quench the reaction and the organics were extracted into EtOAc (3×15 mL), dried (MgSO₄) and concentrated in vacuo (without heating) to give 2-(oxetan-3-yl)propan-1-ol (105 mg, 97%). ¹H NMR (400 MHz, CDCl₃) δ 4.80-4.70 (m, 2H), 4.55 (dt, J=20.0 and 6.4 Hz, 2H), 3.46 (brt, J=4.6 Hz, 2H), 2.98-2.84 (m, 1H), 2.14-2.00 (m, 1H), 0.87 (d, J=6.8 Hz, 3H).

Compounds of Formula (I)

Alkylation of Compounds of Formula (II) to Obtain Compounds of Formula (I)

5-Cyclopropyl-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide (2)

To a solution of Compound (1) (300 mg, 0.75 mmol) in ACN (6 mL) was added potassium carbonate (311 mg, 2.25 mmol) followed by 2-bromoethanol (91.8 μL, 1.30 mmol). The mixture was heated at 85° C. (a thick precipitate was observed after 10 min) and stirred overnight. More potassium carbonate (300 mg, 2.17 mmol) and 2-bromoethanol (90 μL, 1.27 mmol) were added and the mixture was stirred at 90° C. for another 24 hr. The mixture was cooled to RT and the volatiles were removed in vacuo. The residue was suspended in EtOAc (10 mL) and the organics washed with water (10 mL), brine (10 mL) and dried (MgSO₄). The volatiles were removed in vacuo and approximately one sixth of the residue was subjected to column chromatography on silica gel eluting with MeOH:DCM (gradient elution, 0% to 10%) to give partially purified material (50 mg). This material was purified further by column chromatography using C18-reverse phase preparative LCMS eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 100% v/v) to give Compound (2) (7.23 mg). ESI-MS m/z calculated for [M+H]⁺: 444.2; found: 444.2. ¹H NMR (400 MHz, CDCl₃) δ 8.51-8.43 (m, 1H), 8.36 (d, J=0.8 Hz, 1H), 7.82-7.71 (m, 3H), 7.51 (s, 1H), 4.11 (dt, J=11.9, 5.6 Hz, 1H), 3.82-3.76 (m, 2H), 3.76-3.67 (m, 1H), 3.18 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.47 (s, 3H), 2.30 (tt, J=8.3, 5.6 Hz, 1H), 1.06-0.96 (m, 2H), 0.96-0.87 (m, 1H), 0.54-0.41 (m, 1H).

Post-coupling Functionalisation (Halogenation)

5-Cyclopropyl-6-[(2,2-difluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide (3)

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-[(methylsulfonyl)(2-oxoethyl)amino]-2H-indazole-3-carboxamide (i): To a stirred solution of Compound (2) (278 mg) in DCM (6 mL) was added Dess-Martin periodinane (400 mg, 0.94 mmol). The mixture was stirred at room temperature for 1 h and then diluted with DCM (10 mL) and washed with aq. saturated NaHCO₃ solution (10 mL) and water (10 mL). The organic phase was filtered to remove insoluble impurities, dried (MgSO₄) and concentrated in vacuo to afford (i) (276 mg) which was used in the next step without further purification. ESI-MS m/z calculated for [M+MeOH]⁺: 474.2; found: 474.2.

5-Cyclopropyl-6-[(2,2-difluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide (3): To a solution of crude (i) (0.62 mmol) in DCM (4 mL) at 0° C. was added Deoxo-Fluor® (1 mL). The mixture was stirred at RT for 1 h, whereupon aq. saturated NaHCO₃ solution was added and the mixture was extracted into DCM (2×5 mL). The organic phase was dried (MgSO₄) and the volatiles were removed in vacuo. Purification by C18 reverse phase preparative LCMS eluting with ACN:0.1% formic acid in water (gradient elution, 5% to 40% to 50% to 100% v/v) gave Compound (3) (71.9 mg). ESI-MS m/z calculated for [M+H]⁺: 464.2; found: 464.2. ¹H NMR (400 MHz, CDCl₃) δ 8.59-8.45 (m, 1H), 8.36 (s, 1H), 7.84-7.76 (m, 2H), 7.74 (s, 1H), 7.60 (s, 1H), 6.15-5.84 (m, 1H), 4.44-4.25 (m, 1H), 3.99-3.78 (m, 1H), 3.17 (s, 3H), 3.05 (d, J=4.8 Hz, 3H), 2.47 (s, 3H), 2.25-2.13 (m, 1H), 1.12-0.91 (m, 3H), 0.59-0.38 (m, 1H).

Mitsunobu Coupling of Compounds of Formula (II) and (III) to Obtain Compounds of Formula (I)

5-Cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide (4)

To a stirred suspension of Compound 1 (11 mg, 0.03 mmol) and 2-(oxetan-3-yl)ethanol (5.6 mg, 0.06 mmol) in THF (200 μL) was added triphenylphosphine (11 mg, 0.04 mmol) followed by DIAD (8 μL, 0.04 mmol). The suspension dissolved slowly upon stirring. Analysis of the reaction mixture after 2.5 h by LCMS showed the presence of starting material and so further aliquots of triphenylphosphine (5.0 mg, 0.05 mmol) and DIAD (8 μL, 0.04 mmol) were added. After stirring for 2 h, the reaction was diluted with EtOAc (10 mL), the organics washed with water (10 mL), brine (10 mL) and dried (MgSO₄). The organics were concentrated in vacuo and the residue purified by automated column chromatography on silica gel (Biotage SP4, 4 g Grace Resolve cartridge) eluting with acetic acid: DCM (10% v/v, 10 CV) to remove the triphenylphosphine oxide followed by MeOH: DCM (gradient elution, 0% to 20%, 20 CV) to give Compound (4) (7.8 mg, 59%). ESI-MS m/z calculated for [M+H]⁺: 484.2; found: 484.2. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (brs, 1H), 8.36 (s, 1H), 7.83-7.76 (m, 2H), 7.72 (s, 1H), 7.60 (s, 1H), 4.84-4.71 (m, 2H), 4.34 (q, J=6.0 Hz, 2H), 3.74-3.56 (m, 2H), 3.10-2.99 (m, 7H), 2.47 (s, 3H), 2.30 (ddd, J=13.6, 8.3, 5.4 Hz, 1H), 2.07-1.95 (m, 2H), 1.09-0.94 (m, 3H), 0.65-0.56 (m, 1H).

The following compounds were similarly prepared by reference to the general method(s) and/or examples previously described.

TABLE 1 Compounds and characterisation data Observed LCMS m/z No. [M + H]⁺ ¹H NMR  5 428.1 (400 MHz, CDCl₃) δ 8.40-8.24 (m, 2H), 7.86-7.74 (m, 2H), 7.71 (s, 1H), 7.62 (s, 1H), 3.98-3.62 (m, 2H), 3.13-2.93 (m, 6H), 2.46 (s, 3H), 2.41-2.23 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.09-0.89 (m, 3H), 0.73-0.49 (m, 1H).  6 414.1 (400 MHz, CDCl₃) δ 8.35 (d, J = 1.0 Hz, 1H), 8.30 (brd, J = 3.5 Hz, 1H), 7.85-7.73 (m, 2H), 7.71 (s, 1H), 7.66 (s, 1H), 3.36 (s, 3H), 3.08 (s, 3H), 3.05 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H), 2.35-2.25 (m, 1H), 1.08-0.82 (m, 3H), 0.73-0.50 (m, 1H).  7 446.1 (400 MHz, CDCl₃) δ 8.42-8.33 (m, 2H), 7.84-7.76 (m, 2H), 7.75 (s, 1H), 7.67 (s, 1H), 4.67-4.59 (m, 1H), 4.54-4.48 (m, 1H), 4.48- 4.33 (m, 1H), 3.74 (ddt, J = 33.6, 15.3, 3.1 Hz, 1H), 3.17 (s, 3H), 3.04 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H), 2.37-2.24 (m, 1H), 1.09- 1.00 (m, 3H), 0.61-0.50 (m, 1H).  8 448.0 (400 MHz, CDCl₃) δ 8.48-8.46 (m, 1H), 7.94-7.87 (m, 2H), 7.68 (s, 1H), 7.41 (s, 1H), 7.31 (br d, J = 4.2 Hz, 1H), 3.90-3.70 (m, 2H), 3.07 (d, J = 4.9 Hz, 3H), 3.06 (s, 3H), 2.40-2.28 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.08-1.00 (m, 2H), 0.99-0.91 (m, 1H), 0.62-0.53 (m, 1H).  9 434.0 (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 7.94-7.86 (m, 2H), 7.69 (s, 1H), 7.46 (s, 1H), 7.30 (br d, J = 4.5 Hz, 1H), 3.35 (s, 3H), 3.08 (d, J = 5.5 Hz, 3H), 3.08 (s, 3H), 2.36-2.26 (m, 1H), 1.09-0.98 (m, 2H), 0.94-0.78 (m, 1H), 0.64-0.49 (m, 1H). 10 498.2 (400 MHz, CDCl₃) δ 8.52 (s, 1H), 8.36 (s, 1H), 7.79 (d, J = 0.9 Hz, 2H), 7.71 (s, 1H), 7.55 (s, 0.5H), 7.55 (s, 0.5H), 4.62-4.49 (m, 2H), 4.28-4.17 (m, 1H), 3.73-3.53 (m, 2H), 3.06-3.04 (m, 6H), 2.68-2.56 (m, 1H), 2.47 (s, 3H), 2.35-2.24 (m, 1H), 2.07-1.86 (m, 2H), 1.39 (d, J = 6.1 Hz, 1.5H), 1.36 (d, J = 6.1 Hz, 1.5H), 1.09- 0.98 (m, 2H), 0.97-0.87 (m, 1H), 0.64-0.53 (m, 1H). 11 498.2 (400 MHz, CDCl₃) δ 8.64-8.52 (m, 1H), 8.40-8.34 (m, 1H), 7.84- 7.70 (m, 3H), 7.50 (s, 1H), 4.44-4.29 (m, 4H), 3.85-3.63 (m, 2H), 3.09 (s, 3H), 3.07 (d, J = 4 Hz, 3H), 2.48 (s, 3H), 2.34-2.23 (m, 1H), 2.15-1.94 (m, 2H), 1.28 (s, 3H), 1.07-0.96 (m, 2H), 0.92- 0.82 (m, 1H), 0.60-0.46 (m, 1H). 12 420.0 (400 MHz, DMSO) δ 9.19 (s, 1H), 8.64-8.56 (m, 2H), 8.21 (dd, J = 8.7, 2.6 Hz, 1H), 7.95 (d, J = 8.7, 0.6 Hz, 1H), 7.66 (d, 1H), 7.34 (s, 1H), 3.11 (s, 3H), 2.82 (d, J = 4.7 Hz, 3H), 2.32-2.20 (m, 1H), 1.04-0.93 (m, 2H), 0.75-0.66 (m, 2H). 13 420.0 (400 MHz, CDCl₃) δ 10.68 (d, J = 0.9 Hz, 1H), 8.11 (s, 1H), 7.67 (d, J = 0.6 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 3.35 (s, 3H), 3.08 (s, 3H), 3.06 (d, J = 4.7 Hz, 3H), 2.53 (d, J = 1.2 Hz, 3H), 2.34-2.21 (m, 1H), 1.10-0.75 (m, 4H).  14^((a)) 400.0 (400 MHz, CD₃CN) δ 8.53 (ddd, J = 4.9, 1.8, 0.8 Hz, 1H), 8.04 (ddd, J = 8.1, 7.5, 1.8 Hz, 1H), 7.90 (dt, J = 8.1, 0.9 Hz, 1H), 7.82 (d, J = 0.6 Hz, 1H), 7.50 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 3.34 (s, 3H), 3.13 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H), 2.40-2.26 (m, 1H), 0.98 (br m, J = 31.5 Hz, 3H), 0.61 (br s, 1H). 15 448.0 (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.82 (s, 1H), 7.71 (d, J = 0.5 Hz, 1H), 7.59-7.46 (m, 2H), 3.37 (s, 3H), 3.14-3.02 (m, 6H), 2.55- 2.47 (m, 3H), 2.39-2.25 (m, 1H), 1.12-0.78 (m, 3H), 0.74-0.45 (m, 1H). 16 583.1 (400 MHz, CD₃CN) δ 8.39-8.33 (m, 1H), 7.89-7.82 (m, 1H), 7.80 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.37 (br s, 1H), 7.34 (s, 1H), 3.96- 3.87 (m, 2H), 3.70-3.64 (m, 2H), 3.53-3.40 (m, 2H), 3.09 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H), 2.68-2.58 (m, 1H), 2.44 (s, 3H), 2.41-2.29 (m, 1H), 1.92-1.77 (m, 2H), 1.37 (s, 9H), 1.11-0.94 (m, 3H), 0.61-0.49 (m, 1H). 17 525.2 (400 MHz, CD₃CN) δ 8.39-8.33 (m, 1H), 7.89-7.83 (m, 1H), 7.81 (s, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.41-7.32 (m, 2H), 4.20-4.12 (m, 1H), 3.95-3.87 (m, 1H), 3.73-3.66 (m, 3H), 3.49-3.41 (m, 1H), 3.10 (s, 3H), 2.93 (d, J = 4.8 Hz, 3H), 2.74-2.62 (m, 1H), 2.44 (s, 3H), 2.42-2.32 (m, 1H), 1.86 (ddd, J = 14.4, 13.5, 7.1 Hz, 2H), 1.71 (d, J = 1.8 Hz, 3H), 1.11-0.96 (m, 3H), 0.60-0.52 (m, 1H). 18 514.2 (400 MHz, CDCl₃) δ 8.56 (d, J = 4.6 Hz, 1H), 8.37 (s, 1H), 7.83- 7.77 (m, 2H), 7.76 (t, J = 2.3 Hz, 1H), 7.54 (d, J = 9.1 Hz, 1H), 4.65 (d, J = 6.8 Hz, 2H), 4.33 (t, J = 6.7 Hz, 2H), 3.83-3.64 (m, 2H), 3.21 (s, 3H), 3.11-3.02 (m, 6H), 2.48 (s, 3H), 2.42-2.23 (m, 3H), 1.09-0.99 (m, 2H), 0.97-0.85 (m, 1H), 0.63-0.51 (m, 1H). 19 504.0 (400 MHz, CDCl₃) δ 8.53 (s, 1H), 7.98 (s, 2H), 7.77 (s, 1H), 7.52 (s, 1H), 7.38 (s, 1H), 4.89-4.76 (m, 2H), 4.43-4.32 (m, 2H), 3.81- 3.61 (m, 2H), 3.12 (d, J = 6.9 Hz, 3H), 3.09 (s, 3H), 2.45-2.31 (m, 1H), 2.17-1.96 (m, 3H), 1.19-1.00 (m, 3H), 0.73-0.61 (m, 1H). 20 613.0 (400 MHz, CD₃CN) δ 8.34 (dd, J = 1.5, 0.7 Hz, 1H), 7.86-7.72 (m, 3H), 7.37 (s, 1H), 7.28 (br s, 1H), 5.46 (br m, 1H), 4.35-4.28 (m, 2H), 4.28-4.22 (m, 2H), 3.85-3.72 (m, 2H), 3.27 (d, J = 6.4 Hz, 2H), 3.11 (s, 3H), 2.91 (d, J = 4.8 Hz, 3H), 2.42 (s, 3H), 2.39-2.30 (m, 1H), 2.06-1.87 (m, 2H), 1.26 (s, 9H), 1.09-0.95 (m, 3H), 0.65-0.56 (m, 1H). ^((a))Compound 14 may be synthesised from Compound 9 as follows: To a stirred solution of Compound 9 (30 mg, 0.069 mmol) in THF (6 mL) and MeOH (4 mL) was added ammonium formate (22 mg, 0.346 mmol) followed by 10% w/w palladium on carbon (7 mg, 0.01 mmol). After 30 min, the reaction mixture was filtered through a syringe filter (disc filter, 0.45 μm) and the filtrate was concentrated in vacuo. The residual white solid was purified by preparative HPLC/MS (MeCN/0.1% formic acid in water (v/v) - gradient elution) to afford Compound 14 as a white amorphous solid (15 mg, 54%). Biological Data

The in vitro antiviral activity of the compounds of the invention may be determined using the following protocols.

HCV Polymerase Inhibition Assay

HCV polymerase reactions were carried out using a modified method of Howe et al., Antimicrobial Agents and Chemotherapy 2004 48(12): 4813-4821. Reactions contained a final concentration of, 0.5% DMSO, 100 nM, 1b (BK) NS5BΔ21, 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 5 mM MnCl₂, 3 mM DTT, 0.05% BSA, 0.2 U/μL RNasin, 10 μg/mL Poly(rC) template, GTP (at Km) and 0.05 μCi/μL ³³P-GTP in a total reaction volume of 50 μL. Compounds were tested in a three fold dilution series, for example starting from 50 μM. Reactions were initiated with the addition of GTP and terminated after 90 min with 50 μL ice cold 0.2 M EDTA. Terminated reactions were transferred to DEAE 96-well filter plates, unincorporated nucleotides washed from the filters and 50 μL scintillation fluid added prior to reading on a scintillation counter. The compound concentration that reduced ³³P-GTP incorporation by 50% (IC₅₀) was calculated using non-linear regression.

Representative 1b polymerase IC₅₀ (μM) values for selected compounds of the invention in the HCV polymerase inhibition assay are listed as follows where IC₅₀ (μM) values lie in the ranges:

-   A (<0.10 μM): 8, 9 -   B (0.1-0.49 μM): 4, 5, 6, 11, 18, 19 -   C (0.5-0.99 μM): 3, 7, 10, 17 -   D (1.0-10.0 μM): 2, 16     HCV Replicon Assays

A genotype 1b (Con 1) subgenomic replicon cell line based on Blight et al., Science 2000 290: 1972-1974, modified to express a Renilla luciferase reporter gene was used to assess antiviral activity of test compounds. Cell cultures were maintained in a sub-confluent state in DMEM with glutamine, 10% heat-inactivated foetal bovine serum (FBS) and G418 (Geneticin®).

For assay, cells were seeded at a density of 7000 cells/well into 96 well tissue culture trays in culture media lacking G418. Compounds were tested in a three fold dilution series, for example starting from 50 uM. After 72 hours incubation at 37° C. and 5% CO₂ , Renilla luciferase activity was quantified via the Promega Renilla Luciferase or Renilla-Glo™ Luciferase Assay Systems (Promega corporation. The same method was employed for replicon assays using subgenomic genotype 1a (H77) and 2a (JFH-1) replicon cell lines with a seeding cell density of 5000 cells/well for the 2a cell lines.

The compound concentration that reduced luciferase activity by 50% (EC₅₀) was calculated using non-linear regression. Representative genotype 1b EC₅₀ values for selected compounds of the invention are listed as follows where EC₅₀ (μM) values lie in the ranges:

-   A (<0.10 μM): 3, 4, 5, 6, 7, 8, 9, 10, 11, 16, 18, 19 -   B (0.1-0.49 μM): 2, 13, 14, 15, 17 -   C (0.5-0.99 μM):— -   D (1.0-10.0 μM):—     Cytotoxicity Analysis

Cytotoxicity of compounds against genotype 1b replicon cells was determined via metabolism of the vital dye 3-(4,5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, for example see Watanabe et al., Journal of Virological Methods 1994 48:257-265). Plates were prepared as described for the HCV Replicon assay and cytotoxicity of the test article was evaluated after three days. MTT was added to assay plates followed by three hour incubation at 37° C. Wells were aspirated to dryness and the formazan dye dissolved by the addition of isopropanol. Absorbance values were read at 540/690 nm). The compound concentration that reduced cell viability by 50% (CC₅₀) was calculated using non-linear regression. In general, compounds of the invention displayed low cytotoxicity with CC₅₀ values of >50 μM.

Cross-genotype HCV Activity

Cross-genotypic activity of the compounds may be determined in HCV replicon assays for genotypes such as 1b, 1a and 2a as previously described and similarly for genotypes 3a, 4a, 5a, 6a and 7a. Multi-genotype HCV polymerase assays include genotypes such as 1b as previously described and similarly for genotypes 1a, 2a, 3a, 4a, 5a, 6a and 7a.

Compound A containing a 3-pyridyl moiety was also tested for comparative purposes against a selected example of the invention, Compound 5, in the HCV Polymerase Inhibition assay, HCV Replicon assay and Cytotoxicity assay. Compound 5 was shown to be at least 10 times more potent than Compound A in each of the HCV assays tested. Compounds 4, 6, 8, 9, 11, 18 and 19 were tested in the same HCV assays and showed similar levels of activity in each of the HCV assays as Compound 5. The results are provided in Table 2.

5-Cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2-(6-methylpyridin-3-yl)-2H-indazole-3-carboxamide (Compound A)

ESI-MS m/z calculated for [M+H]⁺: 428.2; found: 428.2. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.3, 2.6 Hz, 1H), 7.73 (s, 1H), 7.33 (d, J=9.5 Hz, 2H), 6.00 (s, 1H), 3.82 (qd, J=7.1, 3.3 Hz, 2H), 3.06 (d, J=5.6 Hz, 3H), 3.03 (d, J=4.9 Hz, 3H), 2.66 (s, 3H), 2.44 (tt, J=8.3, 5.4 Hz, 1H), 1.24 (t, J=7.2 Hz, 3H), 1.09 (ddd, J=17.6, 7.0, 5.3 Hz, 2H), 0.98 (s, 1H), 0.57 (d, J=4.7 Hz, 1H).

TABLE 2 HCV Polymerase (NS5B) Inhibition, HCV Replicon (Cell) Activity across Genotypes 1b, 1a and 2a and Cytotoxicity for Compound A against representative compounds of formula (I) Com- NS5B G1b G1b G1a G2a G1b pound (IC₅₀ μM) (EC₅₀ μM) (EC₅₀ μM) (EC₅₀ μM) (CC₅₀ μM) A 3.357 0.774 3.174 3.593 >50 5 0.283 0.030 0.068 0.147 >50 4 0.388 0.054 0.035 0.293 >50 6 0.310 0.004 0.044 0.024 >50 8 0.091 0.009 0.016 0.040 >50 9 0.054 0.008 0.031 0.055 >50 11 0.400 0.028 0.013 0.183 >50 18 0.188 0.056 0.031 0.305 >50 19 0.131 0.021 0.011 0.019 >50 Combination Studies in Replicon Cells

A genotype 1b (Con 1) subgenomic replicon cell line based on Blight et al., Science 2000 290: 1972-1974, modified to express a Renilla luciferase reporter gene may be used to assess synergy of test compounds. Cell cultures were maintained in a sub-confluent state in DMEM with glutamine, 10% heat-inactivated foetal bovine serum (FBS) and G418 (Geneticin®).

For assay, cells are seeded at a density of 7000 cells/well into 96 well tissue culture trays in culture media lacking G418. The compound concentration that reduced luciferase activity by 50% (EC₅₀) is determined independently for each compound and used to set the range of concentrations for the combination experiments. Each compound is tested singly and in combination using either 3-fold or 5-fold serial dilutions above and below the EC₅₀. The ratio of the 2 compounds tested remained fixed across the titration range. Cytotoxicity of individual compounds is assessed independently and the titration range below the compound concentration that reduced cell viability by 50% (CC₅₀). After 72 hours incubation at 37° C. and 5% CO₂ , Renilla luciferase activity is quantified via the Promega Renilla Luciferase Assay System.

Results are analysed and levels of synergy assessed via generation of 3D synergy plots using either MacSynergy™ II (Prichard, M. N., K. R. Aseltine, and C. Shipman, Jr. 1993. MacSynergy II. Version 1.0. User's manual. University of Michigan, Ann Arbor.) or by calculation of a combination index (CI) using the CalcuSyn software package (version 2.1) which performs multiple drug dose-effect calculations using the Median Effect methods (Chou T-C. Drug Combinations Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Research 2010; 70 440-446). This model allows the calculation of a combination index (CI) which is a quantitative definition of an additive effect (CI=1), synergism (CI<1) or antagonism (CI>1) for different drug combinations. Theoretical additive interactions are individually calculated from the dose-response curves for each compound used. This surface is subtracted from the actual dose-response curve to give regions of non-additive interactions. Combination indices can be expressed for different binary combinations of compounds at specific concentrations. Table 3 presents the effects of combining Compounds 6 and 9 separately with:

-   (i) a nucleoside NS5B inhibitor     (4-amino-7-(2-C-methyl-β-D-ribofuranosyl)-pyrrolo[2,1-f][1,2,4]triazine); -   (ii) a NS3/4A protease inhibitor (telaprevir); and -   (iii) an NS5A inhibitor (daclatasvir).     Results shown are averages from three separate experiments.

TABLE 3 Combination Indices Combination (both compounds at previously Combination determined EC₅₀) Index Influence Compound 6 & telaprevir 0.84 ++ Compound 9 & telaprevir 0.39 +++ Compound 6 & daclatasvir 0.41 +++ Compound 9 & daclatasvir 0.36 +++ Compound 6 & nucleoside NS5b inhibitor 0.21 ++++ Compound 9 & nucleoside NS5b inhibitor 0.70 ++ 0.1-0.3 ++++ Strong synergism 0.3-0.7 +++ Synergism 0.7-0.85 ++ Moderate Synergism Aqueous Solubility

Test compounds prepared in DMSO were screened in duplicate over a range of concentrations (1.6-100 ug/mL) in different aqueous media (for example a pH6.5 buffers which are relevant to the stomach and upper regions of the small intestine and therefore important when predicting the amount of drug likely to be in solution following oral administration). Test compounds were serially diluted in 100% DMSO ranging from 10-0.16 mg/mL. These titrated DMSO stocks were then further diluted 1:100 with assay buffer and added to test plates (UV Star Griener 384 well plates), maintaining the DMSO concentration at 1%. The solubility concentration range was determined by interpreting NEPHELOstar laser nephelometery readings taken after a 30 minute incubation at 25° C. A compound is considered to have good solubility when the value is >25 ug/mL.

When the solubility of Compound 5 was compared with Compound A it was found that Compound 5 had good solubility at both pH2 and pH6.5 whereas Compound A was considered to be very poorly soluble at both pHs. Representative Compounds were also tested and showed similar levels of solubility to Compound 5. The results are presented in Table 4.

TABLE 4 Solubility at pH 2 and pH 6.5 (μg/mL) of Compound A against representative compounds of formula (I) pH 2 pH 6.5 Variable Variable Compound (μg/mL) (μg/mL) m of formula (I) R₂ of formula (I) A <1.6 6.3-12.5 — — 5 >100 >100 1 CH₃ (or 2) (or H) 2 50-100 >100 2 OH 3 50-100 50-100 1 CHF₂ (or 2 substituted (or F) with F) 11 50-100 50-100 2 oxetane (substituted with CH₃) 17 50-100 >100 2 azetidine (substituted with C(═O)CH₃) Metabolic Stability Assay

The in vitro metabolic stability of compounds of the invention was tested using human liver microsomes as a preliminary indication of the likely in vivo metabolic clearance. The metabolic stability assay was performed by incubating test compounds individually (1 μM) with human liver microsomes at 37° C. and 0.4 mg/mL protein concentration. The metabolic reaction was initiated by the addition of an NADPH-regenerating system (i.e. NADPH is the cofactor required for CYP450-mediated metabolism) and quenched at various time points over the 60 min incubation period by the addition of acetonitrile. Additional samples with the dual co-factors, NADPH and UDPGA (the latter being the co-factor for glucuronidation), can be included in the incubation for qualitative assessment of the potential for glucuronide formation. Control samples (containing neither NADPH nor UDPGA) were included to monitor for potential degradation in the absence of cofactors. Concentrations of each test compound were determined by LC-MS or UPLC-MS relative to calibration standards. Test compound concentration versus time data were fitted to an exponential decay function to determine the first-order rate constant for substrate depletion. In cases where clear deviation from first-order kinetics was evident, only the initial linear portion of the profile was utilised to determine the degradation rate constant (k). Each substrate depletion rate constant can then be used to calculate: a degradation half-life, an in vitro intrinsic clearance value (CL_(int), in vitro); a predicted in vivo hepatic intrinsic clearance value (CL_(int)) and a predicted in vivo hepatic extraction ratio (E_(H)). The predicted hepatic extraction ratios (E_(H)) obtained were used to classify compounds as low (<0.3), intermediate (0.3-0.7), high (0.7-0.95) or very high (>0.95) extraction compounds. A compound is considered to have good metabolic stability when the E_(H) value is low or intermediate (i.e. E_(H)<0.7). Calculations, scaling parameters and classifications are essentially as described in the literature (for example see (1993) Physiological parameters in laboratory animal and humans. Pharmaceutical Research, 10:1093-1095; (Obach, 1999, Drug Metab. Dispos. 27: 1350-1359).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication, or information derived from it, or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that prior publication, or information derived from it, or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. 

The invention claimed is:
 1. A compound of formula (I), salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof:

wherein Z₁ and Z₂ are each independently selected from C—H, C-halo, C-C₁₋₄alkyl, C-C₁₋₄alkylhalo, C-C₁₋₄alkoxy, C-C₁₋₄alkoxyhalo and N; R₁ is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, halo, C₁₋₄alkylhalo, C₁₋₄alkoxyhalo, C₃₋₇cycloalkyl, C₃₋₇cycloalkenyl, 5-6-membered heterocyclyl and 5-6 membered heteroaryl and wherein alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl and heteroaryl in each occurrence may be optionally substituted; R₂ is H or an optional substituent selected from the group consisting of optionally substituted C₁₋₃alkyl, halo, haloC₁₋₃alkyl, OH, C₁₋₃alkoxyl, haloC₁₋₃alkoxyl, CO₂H, CO₂C₁₋₃alkyl, NH1, NHC₁₋₃alkyl, N(C₁₋₃alkyl), NHC(═O)C₁₋₃alkyl, an optionally substituted C₃₋₇cycloakyl, an optionally substituted C₆₋₁₀aryl, and an optionally substituted 4-10-membered heterocyclyl; R₃ is an optionally substituted 6-membered heteroaryl group containing N in the 2-(ortho) ring position with reference to the point of attachment or R₃ is an optionally substituted 5-membered heteroaryl group containing N in the ring position adjacent to the point of attachment; R is H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, or C₃₋₇cycloalkyl; R₅ in each occurrence is independently H or optionally substituted C₁₋₆alkyl; m represents an integer selected from 0, 1, 2, 3, 4, 5 and 6; and each (CH₂) moiety when present may be independently optionally substituted with one or two substituents; and further when m is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6 then one or more (CH₂) may be replaced with O, C═O, NH, optionally substituted NC₁₋₆alkyl, S, S═O or SO₂.
 2. A compound according to claim 1 wherein R₃ is an optionally substituted 2-pyridyl moiety.
 3. A compound according to claim 1 wherein R₃ is a para-substituted 2-pyridyl moiety.
 4. A compound according to claim 1 wherein R₂ is H.
 5. A compound according to claim 1 selected from the group consisting of: 2) 5-cyclopropyl-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 3) 5-cyclopropyl-6-[(2,2-difluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 4) 5-cyclopropyl-N-methyl-2-(5-methylpyridin-2-yl)-6-{(methylsulfonyl)[2-(oxetan-3-yl)ethyl]amino}-2H-indazole-3-carboxamide; 5) 5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 6) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 7) 5-cyclopropyl-6-[(2-fluoroethyl)(methylsulfonyl)amino]-N-methyl-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 8) 2-(5-chloropyridin-2-yl)-5-cyclopropyl-6-[ethyl(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide; 9) 2-(5-chloropyridin-2-yl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2H-indazole-3-carboxamide; 10) 5-cyclopropyl-N-methyl-6-{[2-(2-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 11) 5-cyclopropyl-N-methyl-6-{[2-(3-methyloxetan-3-yl)ethyl](methylsulfonyl)amino}-2-(5-methylpyridin-2-yl)-2H-indazole-3-carboxamide; 13) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(5-methylthiazol-2-yl)indazole-3-carboxamide; 14) 5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]-2-(2-pyridyl)indazole-3-carboxamide; 15) 2-(5-chloro-4-methyl-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methyl(methylsulfonyl)amino]indazole-3-carboxamide; 16) tert-butyl 3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]azetidine-1-carboxylate; 17) 6-[2-(1-acetylazetidin-3-yl)ethyl-methylsulfonyl-amino]-5-cyclopropyl-N-meth methyl-2-pyridyl)indazole-3-carboxamide; 18) 5-cyclopropyl-6-[2-(3-methoxyoxetan-3-yl)ethyl-methylsulfonyl-amino]-N-methyl-2-(5-methyl-2-pyridyl)indazole-3-carboxamide; 19) 2-(5-chloro-2-pyridyl)-5-cyclopropyl-N-methyl-6-[methylsulfonyl-[2-(oxetan-3-yl)ethyl]amino]indazole-3-carboxamide; 20) tert-butyl N-[[3-[2-[[5-cyclopropyl-3-(methylcarbamoyl)-2-(5-methyl-2-pyridyl)indazol-6-yl]-methylsulfonyl-amino]ethyl]oxetan-3-yl]methyl]carbamate; and salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof.
 6. A pharmaceutical agent comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally another HCV antiviral agent.
 7. A HCV polymerase inhibitor comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally another HCV antiviral agent.
 8. A pharmaceutical composition comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally another HCV antiviral agent.
 9. The pharmaceutical agent according to claim 6 additionally comprising at least one immunomodulatory agent.
 10. The pharmaceutical agent according to claim 6 wherein the HCV antiviral agent is selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.
 11. The pharmaceutical agent according to claim 10 wherein the agent is adapted for oral administration.
 12. A method for the treatment of a Flaviviridae viral infection which comprises administering an effective amount of the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally another HCV antiviral agent to a subject in need thereof.
 13. The method according to claim 12 wherein the administration is oral administration.
 14. The method according to claim 12 wherein the Flaviviridae viral infection is a HCV infection.
 15. A method of inhibiting the RNA-dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to an effective amount of the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof and optionally another HCV antiviral agent.
 16. A method of inhibiting HCV replication comprising exposing a cell infected with HCV to an effective amount of the compound according to claim 1 and optionally another HCV antiviral agent.
 17. A pharmaceutical composition comprising the compound according to claim 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or diastereomers thereof, a pharmaceutically acceptable carrier and optionally another HCV antiviral agent selected from the group consisting of Ribavarin, an NS5B inhibitor, an NS3/4A protease inhibitor and an NS5A inhibitor.
 18. The pharmaceutical composition according to claim 17 additionally comprising at least one immunomodulatory agent.
 19. A method for the treatment of a HCV infection which comprises administering an effective amount of the pharmaceutical composition according to claim 17 to a subject in need thereof.
 20. A process for producing the compound according claim 1 comprising the step of coupling a compound of formula (II):

with a compound of formula (III) under coupling conditions; wherein W is hydroxyl, mesylate, tosylate, triflate or halo; and Z₁, Z₂, R₁, R₂, R₃, R₄, R₅ and (CH)_(m) are as defined in claim
 1. 21. The process according to claim 20 wherein the compound of formula (II) is produced from a compound of formula (IX) using sulfonylation conditions:


22. The process according to claim 21 wherein the compound of formula (IX) is produced by reducing the nitro (NO₂) group of the compound of formula (VIII) to an amino (NH₂) group under reduction conditions:


23. The process according to claim 22 wherein the compound of formula (VIII) is produced by reacting a compound of formula (VII) with a primary amine of formula NH₂—R₄ in the presence of a catalyst and carbon monoxide:


24. The process according to claim 23 wherein the compound of formula (VII) is produced by reacting a compound of formula (VI) with a halogenating reagent:


25. The process according to claim 24 wherein the compound of formula (VI) is produced by reacting a compound of formula (IV) with a compound of formula (V) in the presence of triphenylphosphine:

wherein Y is an independently selected substituent; and q is an integer 0, 1, 2, 3 or
 4. 26. A compound produced by the process according to claim
 20. 27. The compound according to claim 1 wherein R₃ is a para-substituted 2-pyridyl moiety.
 28. The compound according to claim 1 wherein the optionally substituted 4-10-membered heterocyclyl is selected from the group consisting of 4-, 5-, and 6-monocyclic heterocyclyls, 5-6-membered monocyclic heteroaryls; 8-10-membered fused bicyclic heterocyclys and 8-10-membered fused bicyclic heteroaryls. 